RESEARCH ARTICLE
Antiarrhythmic Agents and the Risk of Malignant Neoplasm of Liver and Intrahepatic Bile Ducts Yun-Ping Lim1,2, Cheng-Li Lin3, Yen-Ning Lin1, Wei-Chih Ma1, Wei-Cheng Chen1,4, DongZong Hung1,2, Chia-Hung Kao5,6* 1 Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan 2 Department of Emergency, Toxicology Center, China Medical University Hospital, Taichung, Taiwan 3 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan, 4 Department of Pharmacy, National Cheng Kung University Hospital Dou-Liou Branch, Yunlin, Taiwan, 5 Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan, 6 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan * [email protected]
OPEN ACCESS Citation: Lim Y-P, Lin C-L, Lin Y-N, Ma W-C, Chen W-C, Hung D-Z, et al. (2015) Antiarrhythmic Agents and the Risk of Malignant Neoplasm of Liver and Intrahepatic Bile Ducts. PLoS ONE 10(1): e0116960. doi:10.1371/journal.pone.0116960 Academic Editor: Chiou-Hwa Yuh, National Health Research Institutes, TAIWAN Received: September 1, 2014 Accepted: December 16, 2014 Published: January 15, 2015 Copyright: © 2015 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All data and related metadata are deposited in an appropriate public repository: The study population’s data were from Taiwan NHIRD (http://w3.nhri.org.tw/nhird//date_01.html) are maintained by Taiwan National Health Research Institutes (http://nhird.nhri.org.tw/). The National Health Research Institutes (NHRI) is a non-profit foundation established by the government. Funding: These authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist.
Abstract Background The objective of this study was to determine the association between the use of antiarrhythmic agents and the risk of malignant neoplasm of liver and intrahepatic bile ducts (MNLIHD).
Methods We used the research database of the Taiwan National Health Insurance Program to conduct a population-based, case-control study. We identified 9944 patients with antiarrhythmic history who were first diagnosed as having MNLIHD between 2005 and 2010. We identified an additional 19,497 patients with antiarrhythmic history in the same period who did not develop MNLIHD and were frequency-matched using age, sex, and index year to form a control group. Five commercially available antiarrhythmic agents, amiodarone, mexiletine, propafenone, quinidine, and procainamide, were analyzed.
Results The adjusted odds ratio (OR) of MNLIHD was 1.60 (95% confidence interval [CI], 1.45–1.77) for amiodarone users versus nonamiodarone users. In subgroup analysis, amiodarone use was significantly associated with an increased risk of MNLIHD with an adjusted OR of 18.0 (95% CI, 15.7–20.5) for patients with comorbidities compared to an OR of 2.43 (95% CI, 1.92–3.06) for those without comorbidities. After adjustment for age, sex, statins, anti-diabetes medications, non-steroidal antiinflammatory drugs, propafenone use, quinidine use, and comorbidities, the ORs were 1.49, 1.66, and 1.79 for MNLIHD associated with annual mean defined daily doses of 30, 31–145, and >145, respectively.
PLOS ONE | DOI:10.1371/journal.pone.0116960 January 15, 2015
1 / 11
Antiarrhythmic Agents and Hepatic Cancers
Conclusions The results of the present study indicated that amiodarone might be associated with the development of MNLIHD in a dose-dependent manner, particularly among patients with comorbidities.
Introduction The use of antiarrhythmic medication is recommended in routine clinical practice guidelines as the first-line management of atrial fibrillation (AF) [1]. Antiarrhythmic drugs are administered with the aim of reducing the period and incidence of AF, the need for hospitalization, and the incidence of AF-related mortality. However, numerous limitations have been reported for these drugs, including proarrhythmic and noncardiovascular toxicities, and, more frequently, only modest antiarrhythmic efficacy [2]. Despite these limitations, antiarrhythmics are still widely prescribed for the management of symptomatic AF. Several case reports and reviews have addressed the potential adverse effects associated with these agents, including liver toxicity [3–6], hepatic dysfunction [7, 8], steatohepatitis [9], liver injury [10], and intrahepatic cholestatic jaundice [11]. However, few systemic analyses have been conducted in this setting, and little evidence of an association between the use of antiarrhythmic agents and the risk of developing malignant neoplasm of liver and intrahepatic bile ducts (MNLIHD) has been reported. A large-scale retrospective cohort study conducted in Taiwan revealed a borderline significant increase in cancer mortality among patients assigned to aamiodarone group [12]. Based on a review of the literature, only one relevant longitudinal cohort study has been reported, and no large-scale case-control study to date has addressed the association of MNLIHD with the use of antiarrhythmic drugs in Taiwan. Among MNLIHD, hepatocellular carcinoma (HCC) remained the second leading cause of cancer deaths after lung cancer in Taiwan in 2012, with a mortality rate of 34.9 per 100,000 persons (18.6% of the total cases) [13], and it is therefore critical to address this problem. Accordingly, we conducted a population-based case-control study by using data from the National Health Insurance (NHI) program of Taiwan to evaluate the relationship between the use of antiarrhythmic drugs and the risk of MNLIHD.
Methods The NHI Program was established in Taiwan in 1995. It has enrolled up to 99% of the Taiwanese population and contracted with 97% of all medical providers [14]. The National Health Research Institutes (NHRI) is responsible for managing the insurance claims data reported to the Bureau of Health Insurance. For research purpose, the NHRI compiles all medical claims in the NHI program and releases the database annually to the public. In the NHI program, insurants who suffer from certain major diseases, such as malignancies or autoimmunine diseases, and those who require transplants, can apply for a catastrophic illness certificate. Application for a catastrophic illness certificate for malignancies requires cytological or pathological evidence supporting the diagnosis. The NHI database of catastrophic illness integrates multiple NHI databases to provide comprehensive utilization and enrollment information for all patients with severe diseases who obtained copayment exemption from the NHI program. Diagnostics were coded with the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM).
PLOS ONE | DOI:10.1371/journal.pone.0116960 January 15, 2015
2 / 11
Antiarrhythmic Agents and Hepatic Cancers
Fig. 1 illustrated the sampling scheme in the study. From the Registry of Catastrophic Illness and NHI program databases, we identified arrhythmia (ICD-9-CM codes 426–427) patients newly diagnosed with MNLIHD (ICD-9-CM code 155) in the period from 2005 to 2010 as a case group. Patients who were younger than 20 years of age were excluded. The date of application for MNLIHD was defined as the index date. For each of the MNLIHD patients, we randomly selected 2 arrhythmia patients without MNLIHD from the same period, using the same exclusion criteria, and frequency-matched the case group by using sex and age (5 y a group). A total of 9944 patients with MNLIHD and 19,497 patients without MNLIHD were included in this study. We considered major comorbidities and medications as covariates, such as diabetes (ICD-9-CM code 250), chronic liver disease and cirrhosis (ICD-9-CM codes 571), hepatitis B virus (HBV) infection (ICD-9-CM codes V02.61, 070.20, 070.22, 070.30, 070.32), hepatitis C virus (HCV) infection (ICD-9-CM codes V02.62, 070.41, 070.44, 070.51, 070.54), alcoholism (ICD-9-CM codes 291, 303, 305.00, 305.01, 305.02, 305.03, 790.3,V11.3), medications of statins, anti-diabetics, and non-steroidal antiinflammatory drugs (NSAIDs) at baseline. Five commercially available antiarrhythmic drugs in Taiwan were analyzed: amiodarone, mexiletine, propafenone, quinidine, and procainamide. Medication use records were retrieved from ambulatory and inpatient claims data. According to total supply in days and quantity of amiodarone, we calculated the annual mean defined daily dose (DDD) of amiodarone for amiodarone users (ATC C01BD01). For amiodarone, the annual mean DDD was partitioned into 3 levels based on dose tertile.
Figure 1. Flow chart of participant recruitment in this study. doi:10.1371/journal.pone.0116960.g001
PLOS ONE | DOI:10.1371/journal.pone.0116960 January 15, 2015
3 / 11
Antiarrhythmic Agents and Hepatic Cancers
Sex; age (20–39 y, 40–64y, 65–74y, 75 y); medication history of amiodarone, mexiletine, propafenone, quinidine, and procainamide; and comorbidities were compared between the MNLIHD patients and control patients by using a chi-square test. We used a t test for continuous variables. A univariate and multivariate logistic regression model was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for factors associated with the risk of MNLIHD. Only confound variables found significantly in the univariable model were further included in the multivariable model. The multivariate analysis was performed to adjust for possible confounders (including medication of propafenone, quinidine, and comorbidities of diabetes, chronic liver disease and cirrhosis, HBV infection, HCV infection, and alcoholism, and medications of statins, anti-diabetics, and NSAIDs). All analyses were performed using SAS statistical software for Windows (Version 9.2; SAS Institute, Inc., Cary, NC, USA), and the significance level was set at.05.
Ethics Statement The NHIRD encrypts patient personal information to protect privacy and provides researchers with anonymous identification numbers associated with relevant claim information, including patients’ sex, dates of birth, medical services utilized, and prescriptions. Patient consent is not required for accessing the NHIRD. This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101–012). Our IRB specifically waived the consent requirement.
Results The baseline characteristic profiles of the patients are summarized in Table 1. A total of 29,441 arrhythmia patients aged 20 years were enrolled in this study. Of the MNLIHD cases, 60.5% were men and 72.8% were 65 years of age (Table 1). The mean ages of the MNLIHD patients and non- MNLIHD control patients were 70.6 (10.9) and 70.3 (11.2) years, respectively. The proportion of medication history of amiodarone, propafenone, and quinidine was significantly higher for the MNLIHD patients than for the non- MNLIHD control patients. MNLIHD patients were more likely than control patients to exhibit baseline comorbidities (30.7% for diabetes, 91.5% for chronic liver disease and cirrhosis, 34.0% for HBV infection, 42.9% for HCV infection, and 3.63% for alcoholism) and history of medications (40.8% for anti-diabetics and 99.1% for NSAIDs). Compared with the MNLIHD group, the control group was more likely taking statin (31.4% vs 21.0%). Table 2 lists the crude and adjusted ORs of MNLIHD risk by arrhythmic drugs use and comorbidities. In the univariate logistic analysis, among the antiarrhythmic drugs we observed only amiodarone that was risk factors of MNLIHD (P
Antiarrhythmic Agents and the Risk of Malignant Neoplasm of Liver and Intrahepatic Bile Ducts Yun-Ping Lim1,2, Cheng-Li Lin3, Yen-Ning Lin1, Wei-Chih Ma1, Wei-Cheng Chen1,4, DongZong Hung1,2, Chia-Hung Kao5,6* 1 Department of Pharmacy, College of Pharmacy, China Medical University, Taichung, Taiwan 2 Department of Emergency, Toxicology Center, China Medical University Hospital, Taichung, Taiwan 3 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan, 4 Department of Pharmacy, National Cheng Kung University Hospital Dou-Liou Branch, Yunlin, Taiwan, 5 Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan, 6 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan * [email protected]
OPEN ACCESS Citation: Lim Y-P, Lin C-L, Lin Y-N, Ma W-C, Chen W-C, Hung D-Z, et al. (2015) Antiarrhythmic Agents and the Risk of Malignant Neoplasm of Liver and Intrahepatic Bile Ducts. PLoS ONE 10(1): e0116960. doi:10.1371/journal.pone.0116960 Academic Editor: Chiou-Hwa Yuh, National Health Research Institutes, TAIWAN Received: September 1, 2014 Accepted: December 16, 2014 Published: January 15, 2015 Copyright: © 2015 Lim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All data and related metadata are deposited in an appropriate public repository: The study population’s data were from Taiwan NHIRD (http://w3.nhri.org.tw/nhird//date_01.html) are maintained by Taiwan National Health Research Institutes (http://nhird.nhri.org.tw/). The National Health Research Institutes (NHRI) is a non-profit foundation established by the government. Funding: These authors have no support or funding to report. Competing Interests: The authors have declared that no competing interests exist.
Abstract Background The objective of this study was to determine the association between the use of antiarrhythmic agents and the risk of malignant neoplasm of liver and intrahepatic bile ducts (MNLIHD).
Methods We used the research database of the Taiwan National Health Insurance Program to conduct a population-based, case-control study. We identified 9944 patients with antiarrhythmic history who were first diagnosed as having MNLIHD between 2005 and 2010. We identified an additional 19,497 patients with antiarrhythmic history in the same period who did not develop MNLIHD and were frequency-matched using age, sex, and index year to form a control group. Five commercially available antiarrhythmic agents, amiodarone, mexiletine, propafenone, quinidine, and procainamide, were analyzed.
Results The adjusted odds ratio (OR) of MNLIHD was 1.60 (95% confidence interval [CI], 1.45–1.77) for amiodarone users versus nonamiodarone users. In subgroup analysis, amiodarone use was significantly associated with an increased risk of MNLIHD with an adjusted OR of 18.0 (95% CI, 15.7–20.5) for patients with comorbidities compared to an OR of 2.43 (95% CI, 1.92–3.06) for those without comorbidities. After adjustment for age, sex, statins, anti-diabetes medications, non-steroidal antiinflammatory drugs, propafenone use, quinidine use, and comorbidities, the ORs were 1.49, 1.66, and 1.79 for MNLIHD associated with annual mean defined daily doses of 30, 31–145, and >145, respectively.
PLOS ONE | DOI:10.1371/journal.pone.0116960 January 15, 2015
1 / 11
Antiarrhythmic Agents and Hepatic Cancers
Conclusions The results of the present study indicated that amiodarone might be associated with the development of MNLIHD in a dose-dependent manner, particularly among patients with comorbidities.
Introduction The use of antiarrhythmic medication is recommended in routine clinical practice guidelines as the first-line management of atrial fibrillation (AF) [1]. Antiarrhythmic drugs are administered with the aim of reducing the period and incidence of AF, the need for hospitalization, and the incidence of AF-related mortality. However, numerous limitations have been reported for these drugs, including proarrhythmic and noncardiovascular toxicities, and, more frequently, only modest antiarrhythmic efficacy [2]. Despite these limitations, antiarrhythmics are still widely prescribed for the management of symptomatic AF. Several case reports and reviews have addressed the potential adverse effects associated with these agents, including liver toxicity [3–6], hepatic dysfunction [7, 8], steatohepatitis [9], liver injury [10], and intrahepatic cholestatic jaundice [11]. However, few systemic analyses have been conducted in this setting, and little evidence of an association between the use of antiarrhythmic agents and the risk of developing malignant neoplasm of liver and intrahepatic bile ducts (MNLIHD) has been reported. A large-scale retrospective cohort study conducted in Taiwan revealed a borderline significant increase in cancer mortality among patients assigned to aamiodarone group [12]. Based on a review of the literature, only one relevant longitudinal cohort study has been reported, and no large-scale case-control study to date has addressed the association of MNLIHD with the use of antiarrhythmic drugs in Taiwan. Among MNLIHD, hepatocellular carcinoma (HCC) remained the second leading cause of cancer deaths after lung cancer in Taiwan in 2012, with a mortality rate of 34.9 per 100,000 persons (18.6% of the total cases) [13], and it is therefore critical to address this problem. Accordingly, we conducted a population-based case-control study by using data from the National Health Insurance (NHI) program of Taiwan to evaluate the relationship between the use of antiarrhythmic drugs and the risk of MNLIHD.
Methods The NHI Program was established in Taiwan in 1995. It has enrolled up to 99% of the Taiwanese population and contracted with 97% of all medical providers [14]. The National Health Research Institutes (NHRI) is responsible for managing the insurance claims data reported to the Bureau of Health Insurance. For research purpose, the NHRI compiles all medical claims in the NHI program and releases the database annually to the public. In the NHI program, insurants who suffer from certain major diseases, such as malignancies or autoimmunine diseases, and those who require transplants, can apply for a catastrophic illness certificate. Application for a catastrophic illness certificate for malignancies requires cytological or pathological evidence supporting the diagnosis. The NHI database of catastrophic illness integrates multiple NHI databases to provide comprehensive utilization and enrollment information for all patients with severe diseases who obtained copayment exemption from the NHI program. Diagnostics were coded with the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM).
PLOS ONE | DOI:10.1371/journal.pone.0116960 January 15, 2015
2 / 11
Antiarrhythmic Agents and Hepatic Cancers
Fig. 1 illustrated the sampling scheme in the study. From the Registry of Catastrophic Illness and NHI program databases, we identified arrhythmia (ICD-9-CM codes 426–427) patients newly diagnosed with MNLIHD (ICD-9-CM code 155) in the period from 2005 to 2010 as a case group. Patients who were younger than 20 years of age were excluded. The date of application for MNLIHD was defined as the index date. For each of the MNLIHD patients, we randomly selected 2 arrhythmia patients without MNLIHD from the same period, using the same exclusion criteria, and frequency-matched the case group by using sex and age (5 y a group). A total of 9944 patients with MNLIHD and 19,497 patients without MNLIHD were included in this study. We considered major comorbidities and medications as covariates, such as diabetes (ICD-9-CM code 250), chronic liver disease and cirrhosis (ICD-9-CM codes 571), hepatitis B virus (HBV) infection (ICD-9-CM codes V02.61, 070.20, 070.22, 070.30, 070.32), hepatitis C virus (HCV) infection (ICD-9-CM codes V02.62, 070.41, 070.44, 070.51, 070.54), alcoholism (ICD-9-CM codes 291, 303, 305.00, 305.01, 305.02, 305.03, 790.3,V11.3), medications of statins, anti-diabetics, and non-steroidal antiinflammatory drugs (NSAIDs) at baseline. Five commercially available antiarrhythmic drugs in Taiwan were analyzed: amiodarone, mexiletine, propafenone, quinidine, and procainamide. Medication use records were retrieved from ambulatory and inpatient claims data. According to total supply in days and quantity of amiodarone, we calculated the annual mean defined daily dose (DDD) of amiodarone for amiodarone users (ATC C01BD01). For amiodarone, the annual mean DDD was partitioned into 3 levels based on dose tertile.
Figure 1. Flow chart of participant recruitment in this study. doi:10.1371/journal.pone.0116960.g001
PLOS ONE | DOI:10.1371/journal.pone.0116960 January 15, 2015
3 / 11
Antiarrhythmic Agents and Hepatic Cancers
Sex; age (20–39 y, 40–64y, 65–74y, 75 y); medication history of amiodarone, mexiletine, propafenone, quinidine, and procainamide; and comorbidities were compared between the MNLIHD patients and control patients by using a chi-square test. We used a t test for continuous variables. A univariate and multivariate logistic regression model was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for factors associated with the risk of MNLIHD. Only confound variables found significantly in the univariable model were further included in the multivariable model. The multivariate analysis was performed to adjust for possible confounders (including medication of propafenone, quinidine, and comorbidities of diabetes, chronic liver disease and cirrhosis, HBV infection, HCV infection, and alcoholism, and medications of statins, anti-diabetics, and NSAIDs). All analyses were performed using SAS statistical software for Windows (Version 9.2; SAS Institute, Inc., Cary, NC, USA), and the significance level was set at.05.
Ethics Statement The NHIRD encrypts patient personal information to protect privacy and provides researchers with anonymous identification numbers associated with relevant claim information, including patients’ sex, dates of birth, medical services utilized, and prescriptions. Patient consent is not required for accessing the NHIRD. This study was approved by the Institutional Review Board of China Medical University (CMU-REC-101–012). Our IRB specifically waived the consent requirement.
Results The baseline characteristic profiles of the patients are summarized in Table 1. A total of 29,441 arrhythmia patients aged 20 years were enrolled in this study. Of the MNLIHD cases, 60.5% were men and 72.8% were 65 years of age (Table 1). The mean ages of the MNLIHD patients and non- MNLIHD control patients were 70.6 (10.9) and 70.3 (11.2) years, respectively. The proportion of medication history of amiodarone, propafenone, and quinidine was significantly higher for the MNLIHD patients than for the non- MNLIHD control patients. MNLIHD patients were more likely than control patients to exhibit baseline comorbidities (30.7% for diabetes, 91.5% for chronic liver disease and cirrhosis, 34.0% for HBV infection, 42.9% for HCV infection, and 3.63% for alcoholism) and history of medications (40.8% for anti-diabetics and 99.1% for NSAIDs). Compared with the MNLIHD group, the control group was more likely taking statin (31.4% vs 21.0%). Table 2 lists the crude and adjusted ORs of MNLIHD risk by arrhythmic drugs use and comorbidities. In the univariate logistic analysis, among the antiarrhythmic drugs we observed only amiodarone that was risk factors of MNLIHD (P
